Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.
Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.
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DOI：
10.1038/cddis.2015.62
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发表时间：
2015-03-12
影响因子：
9
通讯作者：
Kashkar H
中科院分区：
文献类型：
--
作者：
Schüll S;Günther SD;Brodesser S;Seeger JM;Tosetti B;Wiegmann K;Pongratz C;Diaz F;Witt A;Andree M;Brinkmann K;Krönke M;Wiesner RJ;Kashkar H
虽然线粒体呼吸链（RC）内的许多致病性变化已与受影响的组织内的细胞凋亡的发生率升高，线粒体功能障碍如何启动凋亡性细胞死亡的机制的见解仍然是未知的。在这项研究中，我们表明，细胞色素c氧化酶（考克斯），代表一个常见的缺陷，发现在线粒体疾病的具体改变，促进线粒体细胞凋亡在氧化应激反应。我们的数据确定了增加的神经酰胺合成酶6（CerS6）的活性作为一个重要的促凋亡反应考克斯功能障碍诱导的化学或遗传方法。CerS6活性升高导致促凋亡C16：0神经酰胺的积累，其促进响应于氧化应激的线粒体凋亡。因此，CerS6的抑制或其特异性敲低降低了COX缺陷细胞对氧化应激的敏感性增加。我们的研究结果为线粒体RC功能障碍如何机械地干扰凋亡机制提供了新的见解。基于其在调节考克斯功能障碍后的细胞死亡中的关键作用，CerS6可能代表用于治疗由考克斯功能障碍引起的线粒体疾病的新靶点。
Although numerous pathogenic changes within the mitochondrial respiratory chain (RC) have been associated with an elevated occurrence of apoptosis within the affected tissues, the mechanistic insight into how mitochondrial dysfunction initiates apoptotic cell death is still unknown. In this study, we show that the specific alteration of the cytochrome c oxidase (COX), representing a common defect found in mitochondrial diseases, facilitates mitochondrial apoptosis in response to oxidative stress. Our data identified an increased ceramide synthase 6 (CerS6) activity as an important pro-apoptotic response to COX dysfunction induced either by chemical or genetic approaches. The elevated CerS6 activity resulted in accumulation of the pro-apoptotic C16 : 0 ceramide, which facilitates the mitochondrial apoptosis in response to oxidative stress. Accordingly, inhibition of CerS6 or its specific knockdown diminished the increased susceptibility of COX-deficient cells to oxidative stress. Our results provide new insights into how mitochondrial RC dysfunction mechanistically interferes with the apoptotic machinery. On the basis of its pivotal role in regulating cell death upon COX dysfunction, CerS6 might potentially represent a novel target for therapeutic intervention in mitochondrial diseases caused by COX dysfunction.
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DOI：
10.18632/aging.100459
发表时间：
2012-05
期刊：
Aging
影响因子：
--
作者：
Favaloro B;Allocati N;Graziano V;Di Ilio C;De Laurenzi V
通讯作者：
De Laurenzi V
影响因子：
5.3
作者：
Diaz, Francisca;Fukui, Hirokazu;Moraes, Carlos T.
通讯作者：
Moraes, Carlos T.
线粒体富含神经酰胺的宏域在辐照后功能化bax。
影响因子：
3.7
作者：
Lee H;Rotolo JA;Mesicek J;Penate-Medina T;Rimner A;Liao WC;Yin X;Ragupathi G;Ehleiter D;Gulbins E;Zhai D;Reed JC;Haimovitz-Friedman A;Fuks Z;Kolesnick R
通讯作者：
Kolesnick R
DOI：
10.1186/2046-2395-3-6
发表时间：
2014
期刊：
Longevity & healthspan
影响因子：
--
作者：
Dai DF;Chiao YA;Marcinek DJ;Szeto HH;Rabinovitch PS
通讯作者：
Rabinovitch PS
影响因子：
64.5
作者：
Chipuk JE;McStay GP;Bharti A;Kuwana T;Clarke CJ;Siskind LJ;Obeid LM;Green DR
通讯作者：
Green DR